Repetitive sequences exist through out the human genome. Trinucleotide repeats represent an important subset of these genomic elements. Initially their presence does not have any pathological consequence but once they expand beyond a tolerable length they become disastrous, resulting in several neurodegenerative diseases such as Huntington disease and fragile X syndrome. It is know that these repeats expand with both age and in subsequent generations. Also, a variety of cellular factors have been implicated in the instability of these sequences, however the complete molecular mechanism underlying their dynamic nature has yet to be defined. I hypothesize that there are unidentified cellular pathways consisting of numerous factors that have yet to be characterized for their ability to influence triplet repeat instability. Also, I suspect that there is a level of cooperation existing among the proteins implicated in this process. Therefore, this proposal aims to discover new factors involved in triplet repeat instability as well as study the interaction between identified pathways both in vitro and in vivo. Specifically, I will screen a chemical library of over 19,000 compounds for their ability to affect repeat contraction in human cells. In addition, I will use siRNA to study the amount of collaboration that exists between cellular pathways involved in repeat instability. The results from this study will provide insight into mechanisms of instability and aid in the development of preventive and therapeutic approaches. The specific aims of this proposal are: Specific Aim 1: Screen for new genes involved in TNR instability. Specific Aim 2: Determine the roles of Topi and Tdp1 in TNR instability. Specific Aim 3: Analyze TNR instability in mice deficient of Xpa Every individual contains trinucleotide repeats in their genome. These sequences can become increased in length. If they expand beyond a certain point they become the source of several devastating diseases. The purpose of my research is to understand the mechanism of this process and develop strategies against it.